Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma

Mateos, María‐Victoria; Dimopoulos, Meletios A.; Cavo, Michèle; Suzuki, Kenshi; Jakubowiak, Andrzej; Knop, Stefan; Doyen, Chantal; Lúcio, Paulo; Nagy, Zsolt; Kaplan, Polina; Pour, Luděk; Cook, Mark; Grosicki, Sebastian; Crepaldi, Andre H; Liberati, Anna Marina; Campbell, Philip; Shelekhova, Tatiana; Yoon, Sung‐Soo; Iosava, Genadi; Fujisaki, Tomoaki; Garg, Mamta; Chiu, Christopher; Wang, Jianping; Carson, Robin; Crist, Wendy; Deraedt, William; Nguyen, Hieu; Qi, Ming; Miguel, Jesús F. San

doi:10.1056/nejmoa1714678

Cited by 797 publications

(682 citation statements)

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“…These findings together suggest that the response with IMP may mature over a longer period compared with VMP and similar response rates can be achieved with IMP followed by ixazomib maintenance and VMP without maintenance. 17,19,23,33 It should also be noted that the weekly IMP regimen used at the RP2D was similar to the less-intense weekly VMP regimen used in the PETHEMA/GEM05 study, followed by bortezomib-based maintenance. 14 In the overall study, the CR rate post-VMP induction was 20%, 14 and in a matched-pairs analysis comparing the PETHEMA/GEM05 and VISTA regimens, the CR rate in PETHEMA/GEM05 patients improved from 19% post-induction to 30% overall, following maintenance.…”

Section: Discussionmentioning

confidence: 99%

“…16,17,23 Most studies of the VMP regimen have utilized a fixed duration of treatment (often approximately 1 year) rather than extended or continuous therapy. 17,19,32,33 Furthermore, in the real-world clinical practice setting, early discontinuations due to toxicities are common. 34 As long-term, continuous therapy is associated with improved outcomes, 9–13 a tolerable, more convenient treatment regimen suitable for long-term use is needed, especially in elderly patients.…”

Section: Discussionmentioning

confidence: 99%

“…14,16,17,19,23,32,33 The CR+VGPR rates post-IMP (43%) and overall (48%) are comparable to rates reported for VMP (41–50% in the phase III VISTA, GIMEMA-MM-03-05, and ALCYONE trials 17,19,33 ), and median PFS (22.1 months) also appeared similar to that reported with VMP and carfilzomib-MP (18.1–27.3 months). 17,19,23,33 Similar CR+VGPR rates (47–49%) and median PFS (21–26 months) were seen with fixed-duration and continuous lenalidomide-dexamethasone (Rd) in the FIRST phase III trial in transplant-ineligible NDMM, 35 and while responses and outcomes appeared better with daratumumab-VMP in ALCYONE (71% CR+VGPR, 18-month PFS 71.6%), 33 and with IRd (58–63%, median PFS 29.4–35.4 months) 29 and bortezomib-Rd (44%, median PFS 43 months) in NDMM patients, 36 these differences should be considered in the context of the addition of daratumumab as a fourth induction agent and as maintenance therapy in ALCYONE, and the inclusion of a high proportion of transplant-eligible patients in the IRd (35%) 29 and VRd (69%) studies. 36 The overall CR rate (28%) seen with IMP plus ixazomib maintenance was also comparable to those reported for VMP without maintenance (24–33% 17,19,23,33 ).…”

Section: Discussionmentioning

confidence: 99%

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A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

et al. 2018

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This phase I/II dose-escalation study investigated the all-oral ixazomib-melphalan-prednisone regimen, followed by single-agent ixazomib maintenance, in elderly, transplant-ineligible patients with newly diagnosed multiple myeloma. Primary phase I objectives were to determine the safety and recommended phase II dose of ixazomib-melphalan-prednisone. The primary phase II objective was to determine the complete plus very good partial response rate. In phase I, patients were enrolled to 4 arms investigating weekly or twice-weekly ixazomib (13 28-day cycles or nine 42-day cycles) plus melphalan-prednisone. In phase II, an expansion cohort was enrolled at the recommended phase II ixazomib dose. Of the 61 patients enrolled, 26 received the recommended phase II dose (ixazomib 4.0 mg [days 1, 8, 15] plus melphalan-prednisone 60 mg/m2 [days 1-4], 28-day cycles). Of the 61 enrolled patients, 36 (13 of 26 in the recommended phase II dose cohort) received single-agent ixazomib maintenance (days 1, 8, 15; 28-day cycles). In phase I, 10/38 patients reported dose-limiting toxicities in cycle 1, including grade 3 and/or 4 neutropenia (n=6) and thrombocytopenia (n=4). Complete plus very good partial response rate was 48% (48% at recommended phase II dose), including 28% (22%) complete response or better; responses deepened during maintenance in 34% (33%) of evaluable patients. After median follow up of 43.6 months, median progression-free survival was 22.1 months. Adverse events were mainly hematologic events, gastrointestinal events, and peripheral neuropathy. This study demonstrates the feasibility, tolerability, and activity of ixazomib-melphalan-prednisone induction and single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma patients. clinicaltrials.gov identifier 01335685.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

et al. 2018

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“…The addition of daratumumab resulted in a 61% reduction in the risk of disease progression or death and an ORR of 83%. 18 Furthermore, registration studies of daratumumab are ongoing in high-risk, smoldering MM and light-chain amyloidosis, thereby exploring the potential of daratumumab across plasma cell dyscrasias. The investigators reported a 63% reduction in the risk of disease progression or death and an ORR of 93%.…”

Section: Discussionmentioning

confidence: 99%

Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma

Chari

Lonial

Mark

et al. 2018

Cancer

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Background Daratumumab is a human CD38‐directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM). Methods A multicenter, open‐label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment‐emergent grade ≥3 adverse events (AEs), serious AEs, and AEs of special interest were collected. Results Three hundred forty‐eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03‐6.0 months). Fifty‐two percent of patients transitioned to commercially‐available daratumumab and 37% discontinued because of progressive disease. Grade ≥3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug‐related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast. Conclusions The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000‐000.

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“…Daratumumab is a first-in-class anti-CD38 monoclonal antibody approved for relapsed and refractory multiple myeloma[1,2] and being tested in both smoldering[3] and newly diagnosed myeloma[4]. CD38 is expressed on airway smooth muscle cells, and infusion related reactions (IRRs) were marked by symptoms (cough, wheezing, rhinorrhea) similar to those of allergic rhinitis.…”

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confidence: 99%